This proposal focuses on the analysis of the molecular mechanisms involved in specification of cell polarity and embryonic axis in Xenopus laevis. Our preliminary data connects Wnt signaling that is essential for axis specification in vertebrate embryos with protein machinery that is involved in the establishment of cell polarity in general. The establishment of cell polarity requires a conserved Par protein complex that antagonizes the product of lethal giant larvae (Lgl), resulting in the accumulation of cell fate determinants in a restricted region of the cell. It is currently unclear how the extracellular environment influences the Par/Lgl complex and whether, in addition to the establishment of cell polarity, the Par-6/Lgl complex may determine the outcome of Wnt signal transduction. To define the molecular crosstalk between Wnt signaling and the Lgl-dependent cell polarity pathway, roles for Lgl and Wnt signaling in the establishment of cell polarity in embryonic ectoderm will be characterized. Proposed studies will evaluate how Wnt signaling regulates Lgl activity, protein levels, and its subcellular localization. The second set of experiments will assess the function of the Par-6 and Lgl gene products in axis specification and morphogenetic movements in Xenopus embryos and their requirement for Wnt signal transduction. These studies will contribute to our long-term goal: to understand how cell and tissue polarity are controlled by extracellular signaling factors during development. Since the Wnt pathways are inappropriately regulated in many cancers, the outcome of proposed experiments should provide insight into the key mechanisms of cell regulation as well as molecular origins of human cancer.